Drug Combination Primes Brain Cancer Cells for Self-Destruction

Drug Combination Primes Brain Cancer Cells for Self-Destruction

Each cell in the human body has the ability to self-destruct if the need arises, whether that need is to remove the webbing between fetal fingers before birth or to remove an infected or defective cell from a healthy body. Cancer cells, however, tend to rewire themselves in a way that cuts this self-destruction fuse.

Wistar’s Dario Altieri, M.D., however, has found a new way to force cancer cells to self-destruct. Low doses of one anti-cancer drug currently in development, called Gamitrinib, sensitize tumor cells to a second drug, called TRAIL, also currently in clinical development as part of an anticancer regimen. Gamitrinib is a chemical inhibitor first developed by Altieri and his colleagues at the University of Massachusetts.

“We found that a low dose of Gamitrinib makes cancer cells susceptible to TRAIL, bypassing many of the mechanisms tumors use to survive,” said Altieri. “Here we have found a new way to combine cancer therapies, one that could be applied to treating many types of cancers, because both of these drugs target different mechanisms of tumor cell survival that revolve around mitochondria.”

Altieri and his colleagues have shown how this combination approach kills tumor cells in both mouse models of glioblastoma and human glioblastoma cells. Glioblastomas are the most common and aggressive form of malignant brain cancer, affecting roughly six out of every 100,000 people. There is currently no effective treatment for glioblastoma, and patients rarely survive more than a year after diagnosis.

As commonly depicted in high school biology texts, mitochondria are the “powerhouses” of the cells, organelles whose main function is to turn sugar into useable energy. What is less commonly known is the role of mitochondria in programmed cell death, or apoptosis, the self-destruct system hardwired into every cell. Apoptosis evolved, in part, as a way for the body to react to extreme stress, a means to sacrifice damaged cells for the greater good of the organism. Cancer cells rely on the mitochondria to provide the energy that rapidly-growing tumors need to survive, but find ways to block the signaling pathways that trigger apoptosis. Many researchers, including Altieri, have looked for ways to force tumor cells to hit this self-destruct switch.

Gamitrinib works by binding to and inhibiting Hsp90 — Heat Shock Protein-90 — a so-called chaperone protein that is highly active in mitochondria and other cellular organelles where it helps regulate and “rescue” other proteins, particularly in times of stress.

“When tumor cells are confronted with lower concentrations of Gamitrinib, they mount a stress-related defensive system, essentially eating damaged mitochondria and altering how genes are turned on and off to compensate for induced defects in the mitochondria,” Altieri said.

Nuclear Factor-kappa Beta (NF-κΒ) broadly promotes survival in tumors by halting the processes that lead to apoptosis. Altieri and his colleagues wanted to see if the suppression of NF-κΒ would provide an opportunity for TRAIL, a small engineered molecule that mimics the signals used to induce apoptosis.

In their experiments, researchers confirmed previous studies which showed that TRAIL alone did not affect glioblastoma in cell and animal models of the disease. TRAIL plus Gamitrinib, however, stimulated damage to mitochondria in tumor cells, which started a cascading series of reactions, culminating in cell death. Preclinical experiments conducted in mouse models of glioblastoma demonstrated that the combination did not cause any detectable toxic side effects.

According to Altieri, the fact that Gamitrinib and TRAIL are in clinical development already may help speed the process that could see eventual clinical trials of the two drugs together. “There is much preclinical work to be done, of course, but we are very interested in laying the groundwork now toward initial clinical trials,” said Altieri.

Going forward, the researchers also plan to delve deeper into the cellular processes at work.

“I find the basic biology of this system fascinating, since here we show how mitochondria, which are the only organelles that have their own DNA, must communicate with the DNA in the cell’s nucleus,” Altieri said. “It is not a well-understood process by any means.”